In 1984 in Ontario, Canada, an outbreak of Salmonella typhimurium food poisoning occurred among police officers who were serving as security guards during a papal visit.¹ Of the 1,608 police officers involved, 432 had acute gastroenteritis. Within three months following the outbreak, 27 of these officers had developed acute arthritis; over the next four months, it resolved in nine of them. The remaining 18 officers had recurrent symptoms or had developed a chronic arthritis on re-evaluation five years later. These officers had developed reactive arthritis, or Reiter's syndrome. Although this condition was once considered benign and self-limited, that may not always be the case. We review the current understanding of this illness and implications for treatment.

Clinical Features

Reactive arthritis is an aseptic inflammatory polyarthritis that usually follows nongonococcal urethritis or infectious dysentery.² The classic triad of arthritis, urethritis and conjunctivitis does not occur in all patients (Table 1). Onset typically occurs one to three weeks following the infection and may present acutely or insidiously. Urethritis is often symptomatic in male patients, usually with a mucopurulent discharge, but sometimes presents as gross hematuria secondary to hemorrhagic cystitis. In female patients, nonspecific cervicitis may occur. However, in either sex, urethritis may be asymptomatic.

The arthritis preferentially involves the lower extremities, is asymmetric and frequently associated with a “sausage” digit. The patient whose foot and ankle are shown in Figure 1 was a journalist on assignment in Africa who developed dysentery and, two weeks later, presented with fever, weight loss, polyarthritis and a “sausage” toe. The presence of enthesitis, inflammation of the ligaments and tendons at the sites of their insertion into the bone, is a helpful distinguishing characteristic. It causes heel pain, Achilles tendonitis or pain at the insertion of the patella tendon into the tibial tubercle. Very large knee effusions, in excess of 100 mL, are not unusual. When these effusions develop rapidly, they frequently result in popliteal cysts that may rupture and cause a pseudo-phlebitis syndrome.

Low back pain is common and is often secondary to inflammatory sacroiliitis. Conjunctivitis is frequently mild, transient and easily missed. Iritis is characteristic of more persistent and chronic disease. Helpful diagnostic skin lesions include keratoderma blennorrhagica, balanitis circinata and painless oral ulcers. Fever and weight loss may be marked.

Cardiac involvement is infrequent; when present, it is characterized by aortic valvular insufficiency and conduction disturbance sometimes leading to heart block.³ Laboratory abnormalities are nonspecific and include anemia, an elevated erythrocyte sedimentation rate or an elevated C-reactive protein level. Examination of joint fluid reveals inflammatory synovitis with 15,000 to 30,000 white blood cells per mm³ (15 to 30 × 10⁹ per L), two thirds of which are typically neutrophils. The joint fluid glucose level is normal, and crystals are not present.

Differential Diagnosis

Reactive arthritis is the most common type of inflammatory polyarthritis in young men. Gonococcal arthritis is more often characterized by acute onset with migratory polyarthralgia that settles in one or more joints and is sometimes associated with tenosynovitis in the small joints of the hands.⁴ A helpful diagnostic clue to gonococcal arthritis is the presence of a pustule with an erythematous base on the hand or foot. Gouty arthritis often affects older men, typically with podagra and severe attacks that are usually limited to a matter of days.

Patients with reactive arthritis and high fever may mimic Still's disease or rheumatic fever. Those with Still's disease will be quite ill, with a high, spiking fever occurring in a double quotidian pattern. A fine evanescent rash on the trunk and marked leukocytosis help to further distinguish the patient with Still's disease. Patients with rheumatic fever tend to present with debilitating migratory polyarthritis and manifest a dramatic and prompt response to treatment with salicylates.

Patients with psoriatic arthritis have many of the same features as those with reactive arthritis. The skin lesions are histologically identical. Patients with psoriasis have fewer constitutional symptoms but, like patients with reactive arthritis, share an asymmetric pattern, sausage digits and distal interphalangeal joint involvement.⁵ Patients with rheumatoid arthritis tend to be female and to have a progressive, additive, symmetric polyarthritis with a predilection for the small joints of the hands and wrists; onset is often insidious. Table 2 lists the differential diagnoses of reactive arthritis.

Causative Organisms

Multiple organisms can trigger Reiter's syndrome following a genitourinary infection or infectious enteritis.⁶ The clinical picture following any of these conditions is virtually identical. Chlamydia trachomatis infection is the most common antecedent of reactive arthritis and accounts for most cases of venereal origin. Reactive arthritis has occurred following a well-documented gonococcal infection, despite adequate treatment of the infection. This finding has led to the use of doxycycline (Vibramycin) or an analog as adjunctive therapy for gonococcal disease, to prevent simultaneous infection with Chlamydia.

Agents causing infectious enteritis leading to reactive arthritis include certain strains of Salmonella, Shigella, Campylobacter and Yersinia (Table 3). The syndrome has even been reported to follow infection with Clostridia difficile.⁷ These organisms share the ability to bind to mucosal surfaces and have prolonged intracellular viability. Patients who go on to develop arthritis frequently have more prolonged episodes of diarrhea,¹ higher antibody levels of the IgA type and persistent titer elevations.

Pathogenesis

Reactive arthritis usually occurs following an infection in a genetically susceptible person. Over two thirds of these patients are HLA-B27 positive. Those who are negative frequently are positive for cross-reacting antigens such as B7, B22, B40 and B42.⁸ A recent study⁹ found a similarity between some peptides found in gram-negative organisms and peptides that are in the binding site of the B27 molecule.

Although these gram-negative organisms may trigger the disease, viable organisms have not been cultured from involved tissues. It was recently reported that the organisms may be persistent in synovial tissue but not in a form that is detectable by routine screening methods.¹⁰

Course

Reactive arthritis was once considered a benign and self-limited condition, but it is, in fact, neither. Of the 27 Ontario police officers who developed reactive arthritis after the food poisoning incident,¹ 18 officers remained symptomatic when reassessed five years later; four patients had radiographic changes and four had disease severe enough to cause them to seek other employment. Fourteen of the 18 officers had evidence of axial disease, including sacroiliitis and spondylitis.

In another study,¹¹ annoying symptoms were present in 22 percent of cases, and sustained disease was present in 34 percent of cases (mean follow-up: 5.6 years). Job changes were necessary in 16 percent of cases, and 11 percent of patients became unemployed. In one of the earliest studies of reactive arthritis, chronic disability was found in 40 of 100 persons who were available for reexamination 25 years after onset of disease.¹¹

Treatment

Symptomatic treatment is accomplished with high doses of a potent nonsteroidal anti-inflammatory drug, such as indomethacin (Indocin). Oral corticosteroids aren't as effective, but intra-articular steroid injections in patients with large knee effusions can be helpful (Table 4). TABLE 4

When Chlamydia is the suspected causative agent, patients may be given doxycycline or an analog for up to three months, but the optimal duration of therapy is unknown. In one study,¹² it was found that when lymecycline, a tetracycline analog, was given for three months, disease duration was shortened to 15 weeks in 50 percent of patients, compared with over 39 weeks' duration in the placebo group.

In another study¹³ of patients with reactive arthritis following a recurrent episode of urethritis, erythromycin or tetracycline therapy limited recurrences to 10 percent, in contrast to a recurrence rate of 37 percent in those who were untreated or who were given penicillin.

In contrast, data on the use of antibiotics following enteric infections are not encouraging. Following Salmonella enteritidis infections among a group of radiologists who were attending a meeting in Sweden, reactive arthritis was no less common or of shorter duration in patients who were treated with antibiotics at an early stage of the Salmonella infection.¹⁴ In an animal model of Yersinia enterocolitica-triggered reactive arthritis, ciprofloxacin (Cipro) prevented the latter disease when it was administered early but was shown to be ineffective after arthritis had already developed.¹⁵

In patients with persistent symptoms, sulfasalazine (Azulfidine) in dosages of 1 to 3 g daily, has been useful.¹⁶ In patients who go on to develop deformities or who show radiographic evidence of erosion or sacroiliitis, methotrexate and azathioprine (Imuran) have been shown to be helpful. Testing for human immunodeficiency virus (HIV) infection is mandatory in patients with persistent symptoms.

Reactive Arthritis in HIV Infection

Reactive arthritis may occur in HIV–infected patients and is sometimes the initial manifestation of the disease.¹⁷ The diagnosis of reactive arthritis should be considered in any patient with an asymmetric oligoarticular polyarthritis. Conversely, HIV infection should be considered in any new case of reactive arthritis where the etiology is at all unclear.

In these patients, arthritis may be severe and may progress rapidly. Azathioprine and methotrexate should not be used when HIV infection is suspected. It is not yet clear if antiretroviral therapy has any effect on the natural history of reactive arthritis in patients being treated for HIV infection.